The objective of present work is to explore combined effect of nateglinide and pioglitazone on diabetic nephropathy. Nateglinide and pioglitazone were administered to the diabetic nephropathic animals as monotherapy and in median and high dose combination for 28 days. Body weight, relative kidney weight, serum and urine biochemical parameters were analyzed along with kidney tissue antioxidant level and histology. Loss in body weight was efficiently controlled by pioglitazone monotherapy and, nateglinide and pioglitazone high dose combination. Nateglinide treatment significantly (P < 0.05-0.001) reduced serum glucose, blood urea nitrogen (BUN), creatinine and insulin along with decrease in urine albumin and increase in creatinine. Both nateglinide and pioglitazone has significantly (P < 0.05-0.01) reduced glomerular filtration rate (GFR). Nateglinide has nonsignificant effect on kidney antioxidant level but pioglitazone has increased (P < 0.05) superoxide dismutase (SOD) level. Both median and high dose combination significantly (P < 0.05-0.001) reduced the elevated level of serum glucose, cholesterol, triglyceride, low density lipoprotein, BUN, creatinine, insulin and glycated haemoglobin. Combination doses were equally effective in decreasing albumin and increasing creatinine urinary excretion with increase in GFR. High dose combination significantly increased catalase, SOD and glutathione level in the kidney tissue. Monotherapy with nateglinide and pioglitazone reduce hyperglycemia and improve kidney functional ability. Both high and median dose combination of nateglinide and pioglitazone was found effective against disturbed serum and urine biochemical parameters. High dose combination was more effective and beneficial in ameliorating kidney pathological damage and oxidative stress in the treatment of diabetic nephropathy.